Machine for plasma purification combined with plasma adsorption-perfusion by using a tricompartmental dialyzer

ABSTRACT

The present invention relates to a machine for performing purification of whole blood that circulates in a flow duct on which there is a stage for filtering plasma from whole blood, which can be functionally arranged in connection to a plasma purification circuit; a stage for dialysis of the whole blood by means of plasma purified in the circuit being provided on the flow duct; the stage comprising a selectively permeable interface for separating part of the whole blood stream of the duct from a countercurrent stream of plasma purified in the purification circuit.

TECHNICAL FIELD

The present invention relates to a machine for plasma purificationcombined with plasma adsorption-perfusion by using a tricompartmentaldialyzer.

The present invention also relates to a blood purification method thatcan be performed with such machine.

BACKGROUND ART

Systemic infections, also known as sepses, caused by massive andpersistent invasion of the circulatory torrent by pathogenicmicroorganisms or by toxins produced by such microorganisms, and septicshock are among the leading causes of mortality in intensive-caresituations.

The pathogenesis of these pathological conditions is known onlypartially.

The various elements that seem to take part in the development of themultiple-organ dysfunction in patients in intensive care includecirculating peptic substances, inflammation mediators, cytokines,bacterial products, endotoxin and other molecules.

Circulating inflammation mediators that have entered the bloodstreamfrom inflammation sites are considered responsible for remote tissuedamage and are seen as decisive factors in the multiple-organdysfunction observed in sepsis.

In recent years, the concept of performing an extracorporealpurification treatment in order to control the development, progressionand damage that this patophysiological process (inflammation mediatorscirculating in the blood) causes in the patient, who passes from a stateof multiple-organ dysfunction to a state of multiple-organ failure, hasgained footing.

Many studies have demonstrated the practical possibility to remove thesemediators by high-volume hemofiltration and/or by means of a process ofadsorption on a specific material (resin). The data available up to nowdemonstrate a significant decrease in these molecules in the blood ofthe patient during treatment.

Some purification techniques have been tested, and continue to betested, in patients affected by sepsis, MODS/MOFS (Multiple OrganDysfunction Syndrome/Multiple Organ Failure Syndrome) and septic shock;the most effective include CPFA (Coupled Plasma Filtration Absorption)and HVHF (High Volume Hemofiltration).

Another extremely important clinical problem relates to patientsaffected by liver failure, who inexorably, as the pathology progresses,develop kidney failure (hepatorenal syndrome) and all the complicationscaused by retention of liver toxins. The accumulation of albumin-boundtoxins has been demonstrated during liver failure; these toxins areresponsible, to variable extents, for multiple-organ dysfunction(kidney, cardiovascular instability, et cetera).

The functions of albumin for transport and as a possible purificationvector have been described in albumin dialysis, in which the removal ofthese molecules improves the clinical condition of the patient.

The best-known and most widely used known extracorporeal device forliver function support is MARS (Molecular Adsorbents Recycling System),which uses albumin that is heterologous with respect to the patient toperform purification by adsorption and by classic dialysis.

The current literature demonstrates that this approach is capable ofimproving patient survival.

Moreover, this type of approach is useful in intoxications caused byexogenous pathogens that are scarcely water-soluble but are plasmaprotein-bound.

In all of these pathologies there is certainly an involvement ofcytokines, and much of the damage that affects the various organs andsystems that are not primarily involved in the basic pathologicalprocess are determined by molecular factors that circulate in the bloodor are dissolved in the plasma water, if water-soluble, oralbumin-bound, if they are not soluble.

DISCLOSURE OF THE INVENTION

The aim of the present invention is to provide a blood purificationdevice that allows to eliminate from blood all the elements that causein patients sepsis, septic shock, multiple-organ dysfunctions, problemsrelated to hepatorenal syndromes, et cetera.

Within this aim, an object of the present invention is to provide ablood purification device that allows to group and utilize in the sametreatment all currently known physical and chemical principles forpurifying the blood of the patient.

Another object of the present invention is to provide a bloodpurification device that can be interfaced easily even with knowndialysis devices or blood purification devices.

Another object of the present invention is to provide a bloodpurification device that is compact.

Another object of the present invention is to provide a bloodpurification device that can be manufactured with known systems andtechnologies.

This aim and these and other objects that will become better apparenthereinafter are achieved by a blood purification device, characterizedin that it comprises a duct for the flow of whole blood along whichthere is a stage for filtering plasma from the whole blood, which isfunctionally arrangeable in connection to a plasma purification circuit,and a stage for whole blood dialysis by means of plasma purified in saidcircuit, this last stage comprising a selectively permeable interfacefor separating at least part of the whole blood stream of said duct froma countercurrent stream of plasma purified in said circuit.

Advantageously, the invention comprises a blood purification method thatcomprises the steps of:

-   -   filtering plasma from whole blood,    -   purifying said plasma filtered from whole blood,    -   purifying said whole blood by flow in countercurrent of a stream        of said purified plasma, separated from the stream of said whole        blood by a permeable interface.

BRIEF DESCRIPTION OF THE DRAWINGS

Further characteristics and advantages of the present invention willbecome better apparent from the following detailed description of apreferred but not exclusive embodiment thereof, illustrated by way ofnon-limiting example in the accompanying drawings, wherein:

FIG. 1 is a diagram of a device according to the invention;

FIG. 2 is a schematic view of a component of a device according to theinvention;

FIGS. 3 a, 3 b and 3 c. are three different sectional views, takenrespectively along the planes IIa-IIa, IIb-IIb, IIc-IIc, of thecomponent of FIG. 2;

FIG. 4 is a functional diagram of the component of FIG. 2.

WAYS OF CARRYING OUT THE INVENTION

With reference to the figures, a blood purification device according tothe invention is generally designated by the reference numeral 10.

The device 10 comprises, in this described embodiment, a filter 12, ofthe type for hemodialysis or the like, which is constituted by aninternal compartment 13 that is crossed by parallel permeablecapillaries 14, of a per se known type, which are made for example ofsynthetic and biocompatible material such as EVAL(ethylene-vinyl-alcohol) or polypropylene (or similar materials).Reference should be made, in this regard, to FIG. 2.

Whole blood flows inside the capillaries 14, which form, together withthe first tube 15 in input to the filter 12 and the second tube 16 inoutput to the filter, a duct 17 for the flow of the whole blood.

The internal compartment 13 is divided, along the extension of thecapillaries 14, into two compartments separated by a wall 13 a,respectively a first compartment 18, which forms a stage 19 forfiltering plasma from whole blood, and a second compartment 20, whichforms a stage 21 for dialysis of whole blood by means of purifiedplasma, which flows in countercurrent with respect to the whole blood.

In particular, the stage 21 for dialyzing blood by means of purifiedplasma comprises a selectively permeable interface, which separates thewhole blood stream of the duct 17 from a countercurrent stream ofpurified plasma that arrives from a plasma purification circuit 23,which is described in greater detail hereinafter.

In practice, such selectively permeable interface is constituted by thecapillaries 14 that are present in the second compartment 20.

The first and second compartments 18 and 20 are mutually connected atthe region where the countercurrent flow of the purified plasma ends.

In particular, the connection is provided by means of a hole 24 formedin the wall 13 a that separates the two compartments 18 and 20.

As mentioned, the first compartment 18 forms the stage 19 for filteringplasma from the whole blood.

The stage 19 for filtering plasma from whole blood is per se of a knowntype.

The first compartment is functionally connected in output to the plasmapurification circuit 23; such circuit in turn is functionally connectedin output downstream of the stage 19 for filtering plasma from wholeblood and the stage 21 for dialyzing whole blood by means of purifiedplasma.

The plasma purification circuit 23 comprises, for example, a device 25for removing water-soluble and dialyzable toxic molecules of a per seknown type, generally used for blood purification but used in this casein an original manner to purify plasma that arrives from the stage 19for filtering plasma from whole blood 19.

The device 25 for removing water-soluble and dialyzable toxic moleculesis composed of modules that perform diffusive processes such ashigh-flux dialysis (although the expression “high-flux plasma dialysis”would be more correct, since it is applied to the plasma, not to theblood), convective-diffusive processes such as hemofiltration orhigh-volume hemofiltration (likewise, plasma filtration and high-volumeplasma filtration), processes for adsorption on a membrane (which arepresent, at least to a minimum extent, in all the previously citedprocesses).

By way of example, as shown in FIG. 1, the device 25 for removingwater-soluble and dialyzable toxic molecules comprises a dialyzer 26that is functionally connected to a dialysate tank 27, a tank for theused dialysate 28, and an infusate tank 29.

The plasma purification circuit 23 comprises, in series to the device 25for removing water-soluble and dialyzable toxic molecules, apurification module of the adsorptive and/or perfusive type 30, of a perse known type, used for the purification of plasma that arrives from thedevice 25 for removing water-soluble and dialyzable toxic molecules.

The purification module of the adsorptive and/or perfusive type 30comprises one or more adsorptive columns and/or one or more perfusivecolumns on carbon.

For circulation of the blood upstream of the filter 12 there is, forexample, a hydraulic pump 31, for example of the peristaltic type.

Likewise, in the plasma purification circuit 23 there are hydraulicpumps 32, preferably of the peristaltic type, in a number andarrangement that is convenient for the particular use of the circuit.

The operation of the invention is described hereinafter.

The whole blood is drawn from the patient by means of a central venousaccess for hemodialysis or arteriovenous fistula and by means of thepropelling force of the peristaltic pump 31 is circulated in the duct 17for the flow of the whole blood with a flux that can vary depending onwhether the device is operating in a continuous or intermittentpurification mode.

The plasma, obtained by filtration from the whole blood in the stage 19for filtering plasma from whole blood, is propelled, again by aperistaltic pump, into the plasma purification circuit 23, where it issubjected to a first purification process by performing, in the device25 for removing water-soluble or dialyzable toxic molecules, a diffusiveor convective-diffusive or pure convective method as described above.

The choice of the method performed (understood as the association of thepurification processes) depends on the conditions of the patient, on thedegree of purification efficiency that one wishes to obtain, andtherefore on the types of molecule that one wishes to eliminate.

The first method has the goal of removing all water-soluble anddialyzable molecules by way of the membrane used in the dialyzer 26 bymeans of a diffusive or diffusive-convective or pure convective processand, to a small extent, by means of an adsorptive process performed onthe surface of said membrane.

Once this purification step has ended, the plasma advances through theadsorptive and/or perfusive purification module 30, such as a specificcolumn chosen according to clinical requirements, where it is subjectedto an adsorption-perfusion process that allows to remove the moleculesbound to plasma albumin or to other plasma components and the moleculesthat cannot be removed by means of the first purification methodperformed in the device 25 for removing water-soluble or dialyzabletoxic molecules; the column can be preceded or not by a carbon column inorder to increase purification. In any case, the effectiveness ofmolecule removal depends on the selectivity of the material used in thecolumn.

This adsorptive process is capable of increasing the purificationeffectiveness of the first treatment and in any case benefits from thefirst treatment in performing a higher purification with respect tomolecules that are scarcely or minimally removable with diffusive orconvective process, even in combination.

Depending on the type of column, it is possible to perform a selectivepurification with respect to bilirubin, bile acids, cytokines, mediummolecular weight molecules, liver toxins retained during liver failure,exogenous toxic factors and various molecules involved in thepathogenesis of sepsis and SIRS (Systemic Inflammatory ResponseSyndrome).

The sequential association of the two purification processes(performed-in the device 25 for removing water-soluble and dialyzabletoxic molecules and in the adsorptive and/or perfusive purificationmodule 30) therefore allows a considerable increase in totalpurification yield.

In the clinical field, for example in case of bilirubinemia, the choiceof high-flux dialysis (convective-diffusive process) allows to removethe direct bilirubin from the plasma, allowing the specific column(adsorptive-perfusive process) to remove with a higher specificity theindirect bilirubin (which is more toxic), since it has to work on aplasma that has a reduced content of direct bilirubin, which in any casereduces the adsorption of indirect bilirubin (purification synergism ofthe two methods used simultaneously).

Once the purification step in the adsorptive and/or perfusivepurification module 30 has ended, the plasma advances along two distinctand separate paths. One fraction returns to the patient through thevenous line (branch 23 a of the circuit 23 that branches out from acommon expander 23 b, of a known type, which ensures continuity offlow), and the other fraction is directed, again under the control of aperistaltic pump, into the stage 21 for dialyzing the whole blood bymeans of purified plasma (second compartment 20), where by flowing incountercurrent with respect to the whole blood that is present in thecapillaries 14 it acts as a dialysate and performs a selective removalof the molecules bound to plasma albumin and to the other plasmacomponents of the whole blood contained in some of the capillaries 14(and therefore in part of the flow duct 17), or in any case of all themolecules that can be captured by said albumin due to bond affinity.

Once the transit in the stage 21 for dialyzing the whole blood by meansof purified plasma has ended, the plasma loaded with toxins (useddialysate) passes, through the hole 13 a, into the first compartment 18,where it joins the plasma filtered in the stage 19 for filtering plasmafrom whole blood, and is returned to the plasma purification circuit 23,where it undergoes the same sequential purification described earlier.

The fraction of purified plasma that returns to the patient is capableof increasing the binding capacity of the plasma with respect to alltoxic factors that have binding affinity with albumin and with the otherplasma components; in this manner, the plasma is capable of capturingthe toxic factors that are present in the tissues and of conveying themto the dialyzer, where they are partly removed by the process ofdialysis with regenerated plasma and partly removed by the purificationprocesses performed on the plasma filtered from the whole blood.

The various streams inside the filter 12 are indicated in FIG. 4.

The arrow (a) designates the blood that flows in the permeablecapillaries (shown in FIGS. 2 and 3).

The arrow (b1) designates the purified plasma that arrives from thecircuit 23 that enters the second compartment 20; the arrow (b2)designates the plasma that, in countercurrent, purifies the whole bloodof the capillaries (acts as a dialysate), the arrow (b3) designates theplasma which, once the capillary blood (which as such is therefore“dirty”) has been purified, passes into the first compartment 18,joining the plasma filtered by the capillaries that are present in saidcompartment; the arrow (b4) designates the “dirty” plasma mixed with thefiltered plasma; the arrow (b5) designates the “dirty” plasma in outputfrom the filter 12 in order to enter the plasma purification circuit 23.The arrow (c1) designates the plasma filtered by the capillaries, andthe arrow (c2) designates the filtered plasma, which together with the“dirty” plasma enters the plasma purification circuit 23.

The plasma of the patient therefore becomes the vector of toxic factors,which can be removed from the tissues by utilizing the binding capacityof plasma albumin and high plasma components, and the capacity of plasmawater to convey water-soluble molecules.

Tissue toxic factors are captured by the plasma and entrained in thebloodstream; the invention extracts the toxic factors from thebloodstream (plasma) by means of the adsorptive-perfusive purificationprocess, from the plasma water by means of the diffusive, convective ordiffusive-convective process, and from the whole blood by means ofdialysis with regenerated plasma.

The processes performed in the device 25 for removing water-soluble anddialyzable toxic molecules of the plasma purification circuit arespecific for molecules that are water-soluble molecules and thereforeare dissolved in the plasma water; if these processes, in addition tobeing diff-usive, also use convection, there is a distinct increase inthe removal of the molecules that have a higher molecular weight and aretherefore less dialyzable by diffusion.

The processes performed in the adsorptive and/or perfusive purificationmodule 30 allow to remove plasma albumin-bound molecules (bilirubin,skatoles, phenols, endogenous benzodiazepines, et cetera), molecules ofhigh molecular weight which as such cannot be dialyzed (such as forexample certain cytokines), and scarcely water-soluble molecules, whichas such cannot be diff-used by means of the plasma water.

The enormous surface of the column exposed to this process allows a highyield of the purification process.

The convective, diffusive or convective-diffusive purification processesare performed according to the standards and methods already in use andcoded in international literature.

The versatility of association among the various processes performed inthe device 25 for removing water-soluble and dialyzable toxic moleculesand the adsorptive-perfusive process allow to obtain and perform thebest treatment for the set goals (removal of cytokines in a septicpatient, removal of uremic and hepatic toxins during hepatorenalsyndrome, removal of bilirubin, bile acids, ammonium, skatoles, phenols,indoles, endogenous benzodiazepines during liver failure, support forpatients with multiple-organ dysfunction or failure syndrome, etcetera).

The association, in the same machine, of all these purificationprocesses allows to achieve control of acid-base and hydroelectrolytichomeostasis, maintaining a high purification of molecules involved insepsis-SIRS (cytokines) and in multiple-organ dysfunction and failuresyndrome.

The versatility, complementarity and synergism in purification of thetreatments allow to support, in the same purification session, patientsaffected by critical pathologies that destabilize highly the entireorganic homeostasis, such as hepatorenal syndrome and sepsis.

The machine can act as an intermittent treatment on demand or as acontinuous therapy for support of particularly unstable patients(hepatorenal syndrome with encephalopathy, septic shock) held inintensive-care units.

The versatility of this machine also allows to provide continuousdiffusive, convective and diffusive-convective treatments (CRRT:Continuous Renal Replacement Therapies) on whole blood.

To convert the machine to this operation it is in fact merely necessaryto use whole blood in the plasma circuit.

The specific adsorption column selected for the treatment can be used ornot on the whole blood depending on its biocompatibility and on therequired purification.

In this configuration, the machine uses the plasma purification circuitfor the whole blood and the device 25 for removing water-soluble anddialyzable toxic molecules is used on the whole blood.

One can conclude that the introduction of the use of the plasma of thepatient (protein and plasma water portion) as a vehicle for toxicfactors and as a vector of the purification process, in addition to thesequential use of the most effective and modern purification methods forpurification of toxic factors, allows to develop a new purificationtechnology that is extremely effective and versatile.

Finally, it is noted that the invention can provide the stage 19 forfiltering plasma from whole blood and the stage 21 for dialyzing thewhole blood by means of purified plasma in separate devices that are notgrouped in a single hemodialysis filter (so as to form in practice asingle tricompartmental dialyzer) and are divided into two compartmentsby a wall, as briefly described hereinafter (no figures are attachedbecause the concept is extremely intuitive and equivalent to thestructure of the purification device described above).

In practice, the stage for filtering plasma from whole blood cancomprise a filter, such as a filter for plasmapheresis or the like,while the stage for dialyzing the whole blood by means of purifiedplasma is constituted by a compartment that is independent andcompletely separate from the plasmapheresis filter and is crossed bypermeable parallel capillaries that delimit part of the duct where thewhole blood flows.

The purified plasma flows in countercurrent within the compartment.

The compartment is functionally connected, by means of a tube, to thefilter in the region where the countercurrent flow of the purifiedplasma ends; the region and the compartment are functionally connectedby means of tubes respectively to an inlet and an outlet of the plasmapurification circuit.

In practice it has been found that the invention thus described achievesthe intended aim and objects.

The invention thus conceived is susceptible of numerous modificationsand variations, all of which are within the scope of the inventiveconcept; all the details may further be replaced with other technicallyequivalent elements.

In practice, the materials employed, so long as they are compatible withthe specific use, as well as the dimensions, may be any according torequirements and to the state of the art.

The disclosures in Italian Patent Application No. PD2003A000076 fromwhich this application claims priority are incorporated herein byreference.

1-13. (canceled)
 14. A blood purification device, comprising a duct forthe flow of whole blood along which there is a stage for filteringplasma from the whole blood, which is functionally arrangeable inconnection to a plasma purification circuit, and a stage for whole blooddialysis by means of plasma purified in said circuit, said stage forwhole blood dialysis comprising a selectively permeable interface forseparating at least part of the whole blood stream of said duct from acountercurrent stream of plasma purified in said circuit.
 15. The bloodpurification device of claim 14, further comprising a filter, which isconstituted by an internal compartment crossed by parallel permeablecapillaries, the space inside said capillaries delimiting at least partof said duct for the flow of said whole blood, said internal compartmentbeing divided, in the direction of the extension of said capillaries,into two separate compartments, respectively a first compartment thatforms said stage for filtering plasma from whole blood and a secondcompartment that forms said stage for dialyzing the whole blood by meansof purified plasma in countercurrent with respect to the whole blood,said first and second compartments being mutually connected at theregion where the countercurrent flow of said purified plasma ends, saidfirst and second compartments being further functionally arrangeable inconnection respectively to an input and an output of said plasmapurification circuit.
 16. The blood purification device of claim 14,wherein said plasma purification circuit is filtered by said stage forfiltering plasma from whole blood, which is functionally connected tosaid stage for dialyzing the whole blood by means of purified plasma,said plasma purification circuit being functionally connected to saidduct downstream of both said stage for filtering plasma from whole bloodand said stage for dialyzing whole blood by means of purified plasma.17. The blood purification device of claim 16, wherein said plasmapurification circuit comprises a device for removing water-soluble anddialyzable toxic molecules, which is generally used to purify blood butis used to purify plasma that arrives from said stage for filteringplasma from whole blood.
 18. The blood purification device of claim 17,wherein said device for removing water-soluble and dialyzable toxicmolecules is composed of modules for performing diffusive processes suchas high-flux dialysis, convective-diffusive processes, purely convectiveprocesses, membrane-based adsorptive processes.
 19. The bloodpurification device of claim 18, wherein said device for removingwater-soluble and dialyzable toxic molecules comprises a dialyzer thatis functionally connected to a dialysate tank, a used dialysate tank,and an infusate tank.
 20. The blood purification device of claim 16,wherein said plasma purification circuit comprises an adsorptive and/orperfusive purification module, used to purify plasma that arrives fromsaid device for removing water-soluble or dialyzable toxic molecules.21. The blood purification device of claim 20, wherein said adsorptiveand/or perfusive purification module comprises one or more adsorptioncolumns and/or one or more perfusion columns on carbon.
 22. A bloodpurification method comprising the steps of: filtering plasma from wholeblood, purifying said plasma filtered from whole blood, purifying saidwhole blood by flow in countercurrent of a stream of said purifiedplasma, separated from the stream of said whole blood by a permeableinterface.
 23. The blood purification method of claim 22, wherein theplasma used in the countercurrent purification of said whole blood isjoined with the plasma filtered from said whole blood part of the plasmapurified after filtration from whole blood is joined to the whole blooddownstream of the filtering of the plasma from whole blood and of thecountercurrent purification.
 24. The blood purification method of claim23, wherein the purification of said plasma filtered from whole bloodprovides for a step for removing water-soluble and dialyzable toxicmolecules by means of one or more processes in mutual combination,chosen among: a diffusive process, a convective-diffusive process, apurely convective process, a membrane-based adsorptive process.
 25. Theblood purification method of claim 24, wherein said processes include:high-flux plasma dialysis, high-volume plasma filtration, plasmafiltration, plasma diafiltration.
 26. The blood purification method ofclaim 25, further comprising, at the end of said step of removingwater-soluble and dialyzable toxic molecules, one or more columnadsorption processes and/or column perfusion processes.